The suprachiasmatic nucleus (SCN) drives circadian clock coherence through intercellular coupling, which is resistant to environmental perturbations. We report that primary cilia are required for ...intercellular coupling among SCN neurons to maintain the robustness of the internal clock in mice. Cilia in neuromedin S-producing (NMS) neurons exhibit pronounced circadian rhythmicity in abundance and length. Genetic ablation of ciliogenesis in NMS neurons enabled a rapid phase shift of the internal clock under jet-lag conditions. The circadian rhythms of individual neurons in cilia-deficient SCN slices lost their coherence after external perturbations. Rhythmic cilia changes drive oscillations of Sonic Hedgehog (Shh) signaling and clock gene expression. Inactivation of Shh signaling in NMS neurons phenocopied the effects of cilia ablation. Thus, cilia-Shh signaling in the SCN aids intercellular coupling.
Bone marrow (BM) niche responds to chemotherapy-induced cytokines secreted from acute lymphoblastic leukemia (ALL) cells and protects the residual cells from chemotherapeutics in vivo. However, the ...underlying molecular mechanisms for the induction of cytokines by chemotherapy remain unknown. Here, we found that chemotherapeutic drugs (e.g., Ara-C, DNR, 6-MP) induced the expression of niche-protecting cytokines (GDF15, CCL3 and CCL4) in both ALL cell lines and primary cells in vitro. The ATM and NF-κB pathways were activated after chemotherapy treatment, and the pharmacological or genetic inhibition of these pathways significantly reversed the cytokine upregulation. Besides, chemotherapy-induced NF-κB activation was dependent on ATM-TRAF6 signaling, and NF-κB transcription factor p65 directly regulated the cytokines expression. Furthermore, we found that both pharmacological and genetic perturbation of ATM and p65 significantly decreased the residual ALL cells after Ara-C treatment in ALL xenograft mouse models. Together, these results demonstrated that ATM-dependent NF-κB activation mediated the cytokines induction by chemotherapy and ALL resistance to chemotherapeutics. Inhibition of ATM-dependent NF-κB pathway can sensitize ALL to chemotherapeutics, providing a new strategy to eradicate residual chemo-resistant ALL cells.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Irritable bowel syndrome (IBS) is a common disorder in gastrointestinal system and impairs the quality of life of the patients. Clostridium butyricum (CB) is a probiotics that has been used in ...several gastrointestinal diseases. The efficacy of CB in treating IBS is still unknown. This prospective, multi-centre, randomized, double-blind, placebo-controlled trial aimed to assess the efficacy and safety of CB in treating diarrhea-predominant IBS (IBS-D) and analyze the fecal microbiota after treatment. Two hundred patients with IBS-D were recruited and were given CB or placebo for 4 weeks. End points included change from baseline in IBS symptoms, quality of life, stool consistency and frequency. Compared with placebo, CB is effective in improving the overall IBS-D symptoms (-62.12 ± 74.00 vs. -40.74 ± 63.67, P = 0.038) as well as quality of life (7.232 ± 14.06 vs. 3.159 ± 11.73, P = 0.032) and stool frequency (-1.602 ± 1.416 vs. -1.086 ± 1.644, P = 0.035). The responder rates are found higher in CB compared with the placebo (44.76% vs. 30.53%, P = 0.042). The change in fecal microbiota was analyzed and function pathways of CB in treating IBS-D were predicted. In conclusion, CB improves overall symptoms, quality of life and stool frequency in IBS-D patients and is considered to be used as a probiotics in treating IBS-D clinically.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Preclinical and clinical studies have suggested a neuroprotective effect of remote ischemic conditioning (RIC), which involves repeated occlusion/release cycles on bilateral upper limb arteries; ...however, robust evidence in patients with ischemic stroke is lacking.
To assess the efficacy of RIC for acute moderate ischemic stroke.
This multicenter, open-label, blinded-end point, randomized clinical trial including 1893 patients with acute moderate ischemic stroke was conducted at 55 hospitals in China from December 26, 2018, through January 19, 2021, and the date of final follow-up was April 19, 2021.
Eligible patients were randomly assigned within 48 hours after symptom onset to receive treatment with RIC (using a pneumatic electronic device and consisting of 5 cycles of cuff inflation for 5 minutes and deflation for 5 minutes to the bilateral upper limbs to 200 mm Hg) for 10 to 14 days as an adjunct to guideline-based treatment (n = 922) or guideline-based treatment alone (n = 971).
The primary end point was excellent functional outcome at 90 days, defined as a modified Rankin Scale score of 0 to 1. All end points had blinded assessment and were analyzed on a full analysis set.
Among 1893 eligible patients with acute moderate ischemic stroke who were randomized (mean SD age, 65 10.3 years; 606 women 34.1%), 1776 (93.8%) completed the trial. The number with excellent functional outcome at 90 days was 582 (67.4%) in the RIC group and 566 (62.0%) in the control group (risk difference, 5.4% 95% CI, 1.0%-9.9%; odds ratio, 1.27 95% CI, 1.05-1.54; P = .02). The proportion of patients with any adverse events was 6.8% (59/863) in the RIC group and 5.6% (51/913) in the control group.
Among adults with acute moderate ischemic stroke, treatment with remote ischemic conditioning compared with usual care significantly increased the likelihood of excellent neurologic function at 90 days. However, these findings require replication in another trial before concluding efficacy for this intervention.
ClinicalTrials.gov Identifier: NCT03740971.
Diabetes mellitus (DM) is a hyperglycemia-related multifactorial condition with an elevated risk of microvascular and microvascular complications associated with this disease. The current ...experimental study was to examine the antidiabetic activity of streptozotocin (STZ)-induced adropin against diabetic rats by altering the PI3K/Akt and insulin signaling pathways. STZ (60 mg/kg) was used for the induction of DM and rats were divided into different groups and received the adropin (20, 40 and 80 mg/kg) and glibenclamide (10 mg/kg) till 28 days. Body weight, plasma insulin, blood glucose and food intake were estimated, respectively. Biochemical enzymes, carbohydrate enzymes, lipid parameters, AMPK and insulin signalling pathway parameters were estimated. GLUT4 and PPARγ expression were also estimated. Oral administration of adropin significantly (p < 0.001) increased the glycogen, glucose-6-phosphatase dehydrogenase, insulin, hexokinase and belittled the blood glucose level, fructose 1-6-biphosphatase, glucose-6-phosphatase at dose dependent manner. Adropin significantly (p < 0.001) reduced the level of triglyceride, cholesterol, low density lipoprotein, very low density lipoprotein and increased the level of high density lipoprotein at dose dependent manner. Adropin significantly (p < 0.001) activated the Akt, IRS-2, IRS-1, IR, p-AKT and PI3k, which are the key modulator molecules of PI3K/Akt, AMPK and insulin signalling pathway in DM rats. The current experimental study confirms the anti-diabetic effect of adropin on DM rats induced by AMPK and insulin signalling pathway against STZ.
The polycomb group protein B lymphoma Mo-MLV insertion region 1 homolog (Bmi-1) is dysregulated in various cancers, and its upregulation strongly correlates with an invasive phenotype and poor ...prognosis in patients with nasopharyngeal carcinomas. However, the underlying mechanism of Bmi-1-mediated invasiveness remains unknown. In the current study, we found that upregulation of Bmi-1 induced epithelial-mesenchymal transition (EMT) and enhanced the motility and invasiveness of human nasopharyngeal epithelial cells, whereas silencing endogenous Bmi-1 expression reversed EMT and reduced motility. Furthermore, upregulation of Bmi-1 led to the stabilization of Snail, a transcriptional repressor associated with EMT, via modulation of PI3K/Akt/GSK-3beta signaling. Chromatin immunoprecipitation assays revealed that Bmi-1 transcriptionally downregulated expression of the tumor suppressor PTEN in tumor cells through direct association with the PTEN locus. This in vitro analysis was consistent with the statistical inverse correlation detected between Bmi-1 and PTEN expression in a cohort of human nasopharyngeal carcinoma biopsies. Moreover, ablation of PTEN expression partially rescued the migratory/invasive phenotype of Bmi-1-silenced cells, indicating that PTEN might be a major mediator of Bmi-1-induced EMT. Our results provide functional and mechanistic links between the oncoprotein Bmi-1 and the tumor suppressor PTEN in the development and progression of cancer.
The rapid outbreak of coronavirus disease 2019 (COVID-19) has been a matter of international concern as the disease is spreading fast 1, 2. Considering that the contagious disease has led to an ...enormous impact globally, there is an urgent need to identify the risk populations with poor prognosis. Ageing is associated with certain changes in pulmonary physiology, pathology and function, during the period of lung infection. Therefore, age-related differences in responsiveness and tolerance become obvious and lead to worse clinical outcomes in elderly individuals 3. Previous studies have mentioned that older COVID-19 patients are at an increased risk of death 4–7. However, the age-related clinical characteristics, disease courses and outcomes other than death in COVID-19 patients remain unclear.
Age significantly determined the clinical features and prognosis of COVID-19. The prognosis was worse in patients older than 60 years, calling for clinicians to pay more attention to patients of this age.
https://bit.ly/34DTI05
The progress of plasmon-based technologies relies on an understanding of the properties of the enhanced electromagnetic fields generated by the coupling nanostrucutres
. Plasmon-enhanced applications ...include advanced spectroscopies
, optomechanics
, optomagnetics
and biosensing
. However, precise determination of plasmon field intensity distribution within a nanogap remains challenging. Here, we demonstrate a molecular ruler made from a set of viologen-based, self-assembly monolayers with which we precisely measures field distribution within a plasmon nanocavity with ~2-Å spatial resolution. We observed an unusually large plasmon field intensity inhomogeneity that we attribute to the formation of a plasmonic comb in the nanocavity. As a consequence, we posit that the generally adopted continuous media approximation for molecular monolayers should be used carefully.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background
Ageing, chronic diseases, prolonged inactivity, and inadequate nutrition pose a severe threat to skeletal muscle health and function. To date, experimental evidence suggests that ...ageing‐related subclinical inflammation could be an important causative factor in sarcopenia. Although inflammatory signalling has been implicated in the pathogenesis of experimental animal models of sarcopenia, few studies have surveyed the clinical association between circulating factors and muscle mass in patients before and after lifestyle interventions. In this study, we evaluated whether proinflammatory cytokines are associated with the onset of sarcopenia, which circulating factors are associated with the severity of sarcopenia, and how these factors change after lifestyle interventions in sarcopenic elderly persons.
Methods
A total of 56 elderly subjects (age ≥ 60 years) with sarcopenia and 56 elderly non‐sarcopenic subjects, who met entry criteria and had given informed consent, were selected from the Peking Union Medical College Hospital multicentre prospective longitudinal sarcopenia study for testing relevant circulating factors. Thirty‐two elderly subjects from the sarcopenic cohort completed a 12 week intensive lifestyle intervention programme with whey supplements (30 g/day) and a personalized resistance training regimen. The levels of proinflammatory cytokines and metabolic hormones, pre‐intensive and post‐intensive lifestyle interventions, were measured.
Results
The sarcopenic group was significantly older (72.05 ± 6.54 years; P < 0.001), more likely to be inactive and female (57.1% of all sarcopenic patients), and had a higher prevalence of type 2 diabetes (16% higher risk). Compared with non‐sarcopenic subjects, serum interleukin (IL)‐6, IL‐18, tumour necrosis factor‐α (TNF‐α), TNF‐like weak inducer of apoptosis (TWEAK), and leptin were significantly higher, while insulin growth factor 1, insulin, and adiponectin were significantly lower in sarcopenic patients (all P < 0.05). Logistic regression analyses revealed that high levels of TNF‐α (>11.15 pg/mL) and TWEAK (>1276.48 pg/mL) were associated with a 7.6‐fold and 14.3‐fold increased risk of sarcopenia, respectively. After adjustment for confounding variables, high levels of TWEAK were still associated with a 13.4‐fold increased risk of sarcopenia. Intensive lifestyle interventions led to significant improvements in sarcopenic patients' muscle mass and serum profiles of TWEAK, TNF‐α, IL‐18, insulin, and adiponectin (all P < 0.05).
Conclusions
High levels of the inflammatory cytokines TWEAK and TNF‐α are associated with an increased risk of sarcopenia, while the metabolic hormones insulin growth factor 1, insulin, and adiponectin are associated with a decreased risk of sarcopenia in our Chinese patient cohort. Intensive lifestyle interventions could significantly improve muscle mass, reduce inflammation, and restore metabolic hormone levels in sarcopenic patients. This trial was registered at clinicaltrials.gov as NCT02873676.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The role of PRKAG2 in the maintenance of heart function is well established, but little is known about how PRKAG2 is regulated in cardiomyocytes. In this study, we investigated the role of the lncRNA ...PRKAG2-AS, which is present at the PRKAG2 promoter, in the regulation of PRKAG2 expression. PRKAG2-AS expression was predominantly nuclear, as determined by RNA nucleoplasmic separation and fluorescence in situ hybridization. Knockdown of PRKAG2-AS in the nucleus, but not the cytoplasm, significantly decreased the expression of PRKAG2b and PRKAG2d. Interestingly, we found that PRKAG2-AS and its target genes, PRKAG2b and PRKAG2d, were reduced in the hearts of patients with ischemic cardiomyopathy, suggesting a potential role for PRKAG2-AS in myocardial ischemia. Indeed, knockdown of PRKAG2-AS in the nucleus resulted in apoptosis of cardiomyocytes. We further elucidated the mechanism by which PRKAG2-AS regulates PRKAG2 transcription by identifying 58 PRKAG2-AS interacting proteins. Among them, PPARG was selected for further investigation based on its correlation and potential interaction with PRKAG2-AS in regulating transcription. Overexpression of PPARG, or its activation with rosiglitazone, led to a significant increase in the expression of PRKAG2b and PRKAG2d in cardiomyocytes, which could be attenuated by PRKAG2-AS knockdown. This finding suggests that PRKAG2-AS mediates, at least partially, the protective effects of rosiglitazone on hypoxia-induced apoptosis. However, given the risk of rosiglitazone in heart failure, we also examined the involvement of PRKAG2-AS in this condition and found that PRKAG2-AS, as well as PRKAG2b and PRKAG2d, was elevated in hearts with dilated cardiomyopathy (DCM) and that overexpression of PRKAG2-AS led to a significant increase in PRKAG2b and PRKAG2d expression, indicating that up-regulation of PRKAG2-AS may contribute to the mechanism of heart failure by promoting transcription of PRKAG2. Consequently, proper expression of PRKAG2-AS is essential for maintaining cardiomyocyte function, and aberrant PRKAG2-AS expression induced by hypoxia or other stimuli may cause cardiac dysfunction.
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